3-Oxo-2,3-dihydro-1H-indazole-4-carboxamide derivatives as PARP-1 inhibitors

Abstract

There are provided 3-oxo-2,3-dihydro-1H-indazole-4-carboxamide derivatives which selectively inhibit the activity of poly (ADP-ribose) polymerase PARP-1 with respect to poly (ADP-ribose) polymerase PARP-2. The compounds of this invention are therefore useful in treating diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.

The invention claimed is: 
     
       1. A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         R 2  is hydrogen, COR 4  or an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         R 3  is hydrogen, halogen, cyano, nitro, NHCOR 4 , COR 4 , NR 5 R 6 , NR 5 COR 4 , OR 7 , SR 7 , SOR 10 , SO 2 R 10 , NHSOR 10 , NHSO 2 R 10 , or an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, heterocyclyl, aryl, heteroaryl, R 8 R 9 N—C 1 -C 6  alkyl and R 8 O—C 1 -C 6  alkyl; 
         R 4  is hydrogen, NR 5 R 7 , OR 7 , SR 7 , or an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, heterocyclyl, aryl, heteroaryl, R 8 R 9 N—C 1 -C 6  alkyl and R 8 O—C 1 -C 6  alkyl; 
         R 5  and R 6  are independently hydrogen, or an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, heterocyclyl, aryl, heteroaryl, R 8 R 9 N—C 1 -C 6  alkyl and R 8 O—C 1 -C 6  alkyl, or R 5  and R 6 , taken together with the nitrogen to which they are bonded, form an optionally substituted heterocyclyl group; 
         R 7  is hydrogen, COR 5 , SOR 10 , SO 2 R 10  or an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, heterocyclyl, aryl, heteroaryl, R 8 R 9 N—C 1 -C 6  alkyl, R 8 O—C 1 -C 6  alkyl, heterocyclyl-C 1 -C 6  alkyl, aryl-C 1 -C 6  alkyl and heteroaryl-C 1 -C 6  alkyl, wherein R 5  is as defined above; 
         R 8  and R 9  are independently hydrogen, COR 4  or an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, heterocyclyl, aryl and heteroaryl, or R 8  and R 9 , taken together with the nitrogen to which they are bonded, form an optionally substituted heterocyclyl group, wherein R 4  is as defined above; 
         R 10  is hydrogen, NR 5 R 6 , OR 7  or an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, heterocyclyl, aryl, heteroaryl, R 8 R 9 N—C 1 -C 6  alkyl and R 8 O—C 1 -C 6  alkyl, wherein R 5 , R 6 , R 7 , R 8  and R 9  are as defined above; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. A compound of formula (I) according to  claim 1 , characterized in that
 R 1  is an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, heterocyclyl, aryl and heteroaryl, the optional substituents being one or more halogen, cyano, NHCOR 4 , COR 4 , NR 5 R 6 , NR 5 COR 4 , OR 7 , oxo (═O) or an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 7  cycloalkyl-C 1 -C 6  alkyl, heterocyclyl-C 1 -C 6  alkyl, aryl-C 1 -C 6  alkyl, heteroaryl-C 1 -C 6  alkyl, R 8 R 9 N—C 1 -C 6  alkyl and R 8 O—C 1 -C 6  alkyl, the optional further substituents being one or more halogen, NHCOR 4 , NR 5 R 6 , NR 5 COR 4 , OR 7 , oxo (═O), SR 7 , or an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, aryl, heterocyclyl, R 8 R 9 N—C 1 -C 6  alkyl and R 8 O—C 1 -C 6  alkyl. 
 
     
     
       3. A compound of formula (I) according to  claim 1 , wherein R 1  is an optionally substituted group selected from C 3 -C 7  cycloalkyl, heterocyclyl, aryl and heteroaryl, the optional substituents being one or more halogen, cyano, NHCOR 4 , COR 4 , NR 5 R 6 , NR 5 COR 4 , OR 7 , oxo (═O) or an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 7  cycloalkyl-C 1 -C 6  alkyl, heterocyclyl-C 1 -C 6  alkyl, aryl-C 1 -C 6  alkyl, heteroaryl-C 1 -C 6  alkyl, R 8 R 9 N—C 1 -C 6  alkyl and R 8 O—C 1 -C 6  alkyl, the optional further substituents being one or more halogen, NHCOR 4 , NR 5 R 6 , NR 5 COR 4 , OR 7 , oxo (═O), SR 7  or an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, aryl, heterocyclyl, R 8 R 9 N—C 1 -C 6  alkyl and R 8 O—C 1 -C 6  alkyl; and
 R 2  is hydrogen, COR 4  or an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, heterocyclyl, aryl and heteroaryl. 
 
     
     
       4. A compound of formula (I) according to  claim 1 , wherein
 R 2  is hydrogen or an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, heterocyclyl, aryl and heteroaryl; and 
 R 3  is hydrogen, halogen, cyano, nitro, NHCOR 4 , NR 5 R 6 , NR 5 COR 4 , OR 7 , or an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, R 8 R 9 N—C 1 -C 6  alkyl and R 8 O—C 1 -C 6  alkyl. 
 
     
     
       5. A compound of formula (I) according to  claim 1 , wherein R 3  is hydrogen, halogen, NHCOR 4 , NR 5 R 6 , NR 5 COR 4 , OR, or an optionally substituted group selected from linear or branched C 1 -C 6  alkyl, R 8 R 9 N—C 1 -C 6  alkyl and R 8 O—C 1 -C 6  alkyl. 
     
     
       6. A compound of formula (I) according to  claim 1 , wherein R 1  is an optionally substituted group selected from heterocyclyl, aryl and heteroaryl, the optional substituents being, one or more COR 4  or an optionally further substituted group selected from linear or branched C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 7  cycloalkyl-C 1 -C 6  alkyl, heterocyclyl-C 1 -C 6  alkyl, aryl-C 1 -C 6  alkyl and heteroaryl-C 1 -C 6  alkyl, the optional further substituents being one or more halogen, OR 7 , oxo (═O) or an optionally substituted group selected from C 1 -C 6  alkyl, aryl, heterocyclyl and R 8 O—C 1 -C 6  alkyl;
 R 2  is hydrogen or a C 1 -C 6  alkyl group; 
 R 3  is hydrogen or halogen; 
 R 4  is OR 7 ; 
 R 7  is hydrogen, optionally substituted C 1 -C 6  alkyl or aryl-C 1 -C 6  alkyl group, substituents being one or more halogen; and 
 R 8  is hydrogen. 
 
     
     
       7. A compound of formula (I) according to  claim 1 , wherein R 1  is an optionally substituted piperidinyl or phenyl group, the optional substituents being, one or more, COR 4  or an optionally further substituted group selected from methyl, ethyl, propyl, cyclohexyl, cyclopentyl, cyclobutyl, morpholinyl, piperazinyl, pyrazolyl, cyclohexyl-methyl, cyclohexenyl-methyl, piperidinyl-methyl, benzyl, pyridyl-methyl, pyrrolyl-methyl, pyrazolyl-methyl, imidazolyl-methyl, thienyl-methyl, indolyl-methyl, thiazolyl-methyl and furyl-methyl, the optional further substituents being one or more bromine, fluorine, chlorine, isopropyl, methyl, phenyl, morpholinyl, piperidinyl, hydroxy-methyl, OR 7 , or oxo (═O);
 R 2  is hydrogen or a methyl group; 
 R 3  is hydrogen or fluorine; 
 R 4  is OR 7 ; and 
 R 7  is hydrogen, an optionally substituted methyl, tert-butyl or benzyl group, the substituents being one or more fluorine. 
 
     
     
       8. A compound of formula (I) or a salt thereof, selected from the group consisting of:
 3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-cyclopentylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-cyclohexylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-cyclohexylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-cyclopentylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-methylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 1-methyl-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide, 
 1-methyl-2-(1-methylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-ethylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 3-oxo-2-(1-propylpiperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-ethylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 1-methyl-3-oxo-2-[1-(propan-2-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 3-oxo-2-[1-(propan-2-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-cyclobutylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-cyclobutylpiperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-cyclobutylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-cyclobutylpiperidin-4-yl)-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 6-fluoro-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide, 
 6-fluoro-1-methyl-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-cyclohexylpiperidin-4-yl)-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-cyclohexylpiperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-[1-(4,4-dichlorocyclohexyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 6-chloro-2-(1-cyclohexylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-cyclohexylazetidin-3-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-cyclohexylazetidin-3-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 6-chloro-2-(1-cyclohexylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-cyclohexylazetidin-3-yl)-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-[1-(cyclohexylmethyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-benzylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-[1-(cyclohexylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-benzylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 3-oxo-2-(1-phenylpiperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide, 
 1-methyl-3-oxo-2-(1-phenylpiperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide, 
 6-fluoro-1-methyl-3-oxo-2-[4-(piperidin-4-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 3-oxo-2-[4-(piperidin-4-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 1-methyl-3-oxo-2-[4-(piperidin-4-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 6-fluoro-1-methyl-3-oxo-2-(1-phenylpiperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide, 
 3-oxo-2-[1-(thiophen-3-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 3-oxo-2-[1-(1H-pyrrol-3-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 6-fluoro-1-methyl-3-oxo-2-[1-(thiophen-3-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 1-methyl-3-oxo-2-[1-(1H-pyrrol-3-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-[1-(furan-3-ylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 3-oxo-2-[1-(pyridin-4-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-[1-(furan-3-ylmethyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 1-methyl-3-oxo-2-[1-(1H-pyrrol-2-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 3-oxo-2-[1-(pyridin-3-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 1-methyl-3-oxo-2-[1-(pyridin-4-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 1-methyl-3-oxo-2-[1-(pyridin-3-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 6-fluoro-1-methyl-3-oxo-2-[1-(pyridin-4-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 6-fluoro-1-methyl-3-oxo-2-[1-(pyridin-3-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 3-oxo-2-[4-(pyridin-4-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 1-ethyl-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-(1-cyclohexylpiperidin-4-yl)-1-ethyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 1-methyl-3-oxo-2-[4-(pyridin-4-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 1-ethyl-6-fluoro-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide, 
 3-oxo-2-[4-(pyridin-3-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 6-fluoro-3-oxo-2-[4-(pyridin-3-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 6-fluoro-1-methyl-3-oxo-2-[4-(pyridin-3-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 3-oxo-2-[1-(thiophen-2-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 1-methyl-3-oxo-2-[1-(thiophen-2-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-[1-(cyclohex-3-en-1-ylmethyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-[1-(cyclohex-3-en-1-ylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, 
 2-[1-(furan-2-ylmethyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, and 
 2-[1-(furan-2-ylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide. 
 
     
     
       9. A process for the preparation of a compound of formula (I) as defined in  claim 1 , which process comprises one of the following steps:
 Step a) halogenating a compound of formula (VII): 
 
       
         
           
           
               
               
           
         
         wherein Hal 1  is halogen such as Cl, Br, I and R 3  is as defined in  claim 1 ; 
         Step b) coupling the resultant compound of formula (VI): 
       
       
         
           
           
               
               
           
         
         wherein Hal 2  is halogen such as Cl, Br, I, different from Hal 1 , and R 3  and Hal 1  are as defined above with a suitable hydrazine (IX): 
       
       
         
           
           
               
               
           
         
         wherein T is linear or branched C 1 -C 6  alkyl or aryl C 1 -C 6  alkyl group and R 1  is as defined in  claim 1 ; 
         Step c) cyclizing the resultant compound of formula (V): 
       
       
         
           
           
               
               
           
         
         wherein Hal 1 , Hal 2 , T, R 1  and R 3  are as defined above; 
         either 
         Step d) cyano-de-halogenating the resultant compound of formula (IV): 
       
       
         
           
           
               
               
           
         
         wherein Hal 1 , T, R 1  and R 3  are as defined above; 
         or 
         Step f′) first, removing the nitrogen protecting group of a compound of formula (IV) as defined above; 
         Step d′) then cyano-de-halogenating the resultant compound of formula (X): 
       
       
         
           
           
               
               
           
         
         wherein R 2  is hydrogen and Hal 1 , R 1 , and R 3  are as defined above; 
         either 
         Step e) first hydrolyzing the compound of formula (III) obtained in step d): 
       
       
         
           
           
               
               
           
         
         wherein T, R 1  and R 3  are as defined above; 
         Step f) then removing the nitrogen protecting group of the resultant compound of formula (I): 
       
       
         
           
           
               
               
           
         
         wherein R 2  is COR 4 , wherein R 4  is OR 7  and R 7  is linear or branched C 1 -C 6  alkyl or aryl-C 1 -C 6  alkyl; and R 1  and R 3  are as defined above, to give the corresponding compound of formula (I) wherein R 2  is hydrogen, and R 1  and R 3  are as defined above; 
         or 
         Step f′) first, removing nitrogen protecting group of a compound of formula (III) obtained in step d); 
         Step e′) then hydrolyzing the resultant compound of formula (VIII): 
       
       
         
           
           
               
               
           
         
         wherein R 2  is hydrogen and R 1  and R 3  are as defined above, to give a compound of formula (I) wherein R 2  is hydrogen and R 1  and R 3  are as defined above; 
         optionally converting a compound of formula (I) into a different compound of formula (I) by known chemical reactions; and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof or converting a salt into a free compound of formula (I). 
       
     
     
       10. A method for treating diseases mediated by PARP-1 protein which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I), as defined in  claim 1 , wherein the disease is selected from the group consisting of cancer, cardiovascular diseases, nervous system injury and inflammation. 
     
     
       11. The method according to  claim 10  wherein the cancer is carcinomas, bladder, breast, colon, kidney, liver, lung, small cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, skin, and squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkitt's lymphoma; hematopoietic tumors of myeloid lineage, acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, astrocytoma neuroblastoma, glioma and schwannomas; melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer and Kaposi's sarcoma. 
     
     
       12. The method according to  claim 11  which provides tumor angiogenesis and metastasis inhibition. 
     
     
       13. The method according to  claim 10  wherein the mammal in need thereof is a human. 
     
     
       14. An in vitro method for selectively inhibiting PARP-1 protein activity which comprises contacting the said protein with an effective amount of a compound of formula (I) as defined in  claim 1 . 
     
     
       15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in  claim 1 , and at least one pharmaceutically acceptable excipient, carrier or diluent. 
     
     
       16. A pharmaceutical composition according to  claim 15  further comprising one or more chemotherapeutic agents. 
     
     
       17. The pharmaceutical composition according to  claim 16 , wherein the chemotherapeutic agent is an alkylating agent. 
     
     
       18. The pharmaceutical composition according to  claim 17 , wherein the alkylating agent is temozolomide. 
     
     
       19. A product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in  claim 1 , and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy. 
     
     
       20. A product according to  claim 19 , wherein the chemotherapeutic agent is an alkylating agent. 
     
     
       21. A product according to  claim 20 , wherein the alkylating agent is temozolomide.